Asthma affects about 15 million individuals in the U.S., and its prevalence and severity are rising. Asthma is recognized as an inflammatory condition of the airways in which eosinophils, basophils, and mast cells are prominent. The objective of this project is to investigate the role(s) of the leukocyte immunoglobulin-like receptors (LIRs) in asthma. The LIRs comprise a family of immunoregulatory cell surface receptors with both activating and inhibitory members. We have shown that eosinophils and basophils express LIR3 (inhibitory) and LIR7 (activating); eosinophils and basophils of about 30% of donors also express LIR1 (inhibitory) or LIR2 (inhibitory), which are receptors for MHC class I. In vitro culture-derived progenitor mast cells express LIR2, LIR3, and LIR7. Cross-linking of LIR7 on human eosinophils elicited the release of eosinophil-derived neurotoxin, leukotriene (LT) C4 biosynthesis, and the release of preformed IL-12, but not IL-4. Cross-linking of LIR7 on human basophils elicited histamine release, LTC4 biosynthesis, and IL-4 generation in quantities comparable to those elicited by signaling through the high affinity Fc receptor for IgE (Fc-epsilonRI). Simultaneous cross-linking of LIR3 attenuated activation by both LIR7 and Fc-epsilonRI. The regulation of the inflammatory response to innate or adaptive stimuli requires both activating and inhibitory signals. The central hypothesis of this project is that the LIRs regulate the activation of eosinophils, basophils, and mast cells and thereby the effector arm of the inflammatory response in asthma. Specifically, we propose the following: The cytokine profile derived by LIR7 will accommodate a role for the basophil in amplifying Th2 responses and for the eosinophil in tissue remodeling. The inhibitory LIRs will attenuate secretory granule exocytosis and lipid mediator release in response to both innate and adaptive signals in eosinophils, basophils, and mast cells. In contrast, the inhibitory LIRs, rather than shutting down all cytokine synthesis, will alter the profile of cytokines elicited by an activating receptor. Cognate recognition of MHC class I by inhibitory LIR1 and LIR2 can set the threshold and amplitude of activation. We further suggest that asthmatic inflammation is associated with dysregulation of expression and/or function of one or more LIRs to favor a proinflammatory outcome. We will therefore compare the expression and function of LIRs between basophils, eosinophils, and mast cells from normal donors and cells from individuals with asthma. We will examine LIR expression in the airways of asthmatic and normal individuals.